Priya R, Sumitha Rajendrarao, Doss C George Priya, Rajasekaran C, Babu S, Seenivasan R, Siva R
Plant Biotechnology, School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu, India.
Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India.
Pharmacogn Mag. 2015 Oct;11(Suppl 3):S414-22. doi: 10.4103/0973-1296.168947.
Acquired immunodeficiency syndrome caused by human immunodeficiency virus (HIV) is an immunosuppressive disease. Over the past decades, it has plagued human health due to the grave consequences in its harness.
For this reason, anti-HIV agents are imperative, and the search for the same from natural resources would assure the safety.
In this investigation we have performed molecular docking, molecular property prediction, drug-likeness score, and molecular dynamics (MD) simulation to develop a novel anti-HIV drug. We have screened 12 alkaloids from a medicinal plant Toddalia asiatica for its probabilistic binding with the active site of the HIV-1-reverse transcriptase (HIV-1-RT) domain (the major contributor to the onset of the disease).
The docking results were evaluated based on free energies of binding (ΔG), and the results suggested toddanol, toddanone, and toddalenone to be potent inhibitors of HIV-1-RT. In addition, the alkaloids were subjected to molecular property prediction analysis. Toddanol and toddanone with more rotatable bonds were found to have a drug-likeness score of 0.23 and 0.11, respectively. These scores were comparable with the standard anti-HIV drug zidovudine with a model score 0.28. Finally, two characteristic protein-ligand complexes were exposed to MD simulation to determine the stability of the predicted conformations.
The toddanol-RT complex showed higher stability and stronger H-bonds than toddanone-RT complex. Based on these observations, we firmly believe that the alkaloid toddanol could aid in efficient HIV-1 drug discovery.
In the present study, the molecular docking and MD simulations are performed to explore the possible binding mode of HIV 1 RT with 12 alkaloids of T. asiatica. Molecular docking by AutoDock4 revealed three alkaloids toddanol, toddanone, and toddalenone with highest binding affinity towards HIV 1 RT. The drug likeness model score revealed a positive score for toddanol and toddanone which is comparable to the drug likeness score of the standard anti HIV drug zidovudine. Results from simulation analysis revealed that toddanol RT complex is more stable than toddanone RT complex inferring toddanol as a potential anti HIV drug molecule. Abbreviations used: HIV: Human immunodeficiency virus, HIV 1 RT: HIV 1 reverse transcriptase, RNase H: Ribonuclease H, MD: Molecular dynamics, PDB: Protein databank, RMSD: Root mean square deviation, RMSF: Root mean square fluctuation.
人类免疫缺陷病毒（HIV）引起的获得性免疫缺陷综合征是一种免疫抑制性疾病。在过去几十年里，它因其严重后果一直困扰着人类健康。
因此，抗HIV药物势在必行，从自然资源中寻找此类药物可确保安全性。
在本研究中，我们进行了分子对接、分子性质预测、类药性评分和分子动力学（MD）模拟，以开发一种新型抗HIV药物。我们从药用植物飞龙掌血中筛选了12种生物碱，研究其与HIV-1逆转录酶（HIV-1-RT）结构域（该疾病发病的主要因素）活性位点的可能结合情况。
根据结合自由能（ΔG）评估对接结果，结果表明飞龙掌血醇、飞龙掌血酮和飞龙掌血烯酮是HIV-1-RT的有效抑制剂。此外，对这些生物碱进行了分子性质预测分析。发现具有更多可旋转键的飞龙掌血醇和飞龙掌血酮的类药性评分分别为0.23和0.11。这些评分与标准抗HIV药物齐多夫定的模型评分0.28相当。最后，对两个特征性蛋白质-配体复合物进行MD模拟，以确定预测构象的稳定性。
飞龙掌血醇-RT复合物比飞龙掌血酮-RT复合物表现出更高的稳定性和更强的氢键。基于这些观察结果，我们坚信生物碱飞龙掌血醇有助于高效发现抗HIV-1药物。
在本研究中，进行了分子对接和MD模拟，以探索HIV-1 RT与飞龙掌血12种生物碱的可能结合模式。AutoDock4进行的分子对接显示，三种生物碱飞龙掌血醇、飞龙掌血酮和飞龙掌血烯酮对HIV-1 RT具有最高的结合亲和力。类药性模型评分显示飞龙掌血醇和飞龙掌血酮的评分呈阳性，与标准抗HIV药物齐多夫定的类药性评分相当。模拟分析结果表明，飞龙掌血醇-RT复合物比飞龙掌血酮-RT复合物更稳定，这表明飞龙掌血醇是一种潜在的抗HIV药物分子。使用的缩写：HIV：人类免疫缺陷病毒，HIV-1 RT：HIV-1逆转录酶，RNase H：核糖核酸酶H，MD：分子动力学，PDB：蛋白质数据库，RMSD：均方根偏差，RMSF：均方根波动。
